tbuckley/cabot-search huggingface dataset:
Abstract 6375: Augmented intelligence to define drug targets associated with triple negative breast cancer (TNBC) metabolic reprogramming
Authors: Sarah Jenna, Benjamin Boucher, Liebaut Dudragne, Abdoulaye Baniré Diallo
Journal: Cancer Research (2022)

Abstract Introduction: Basal-like breast cancer (BLBC; TNBC) cells use aerobic glycolysis at a higher rate than Luminal A (LumA) cells. Metabolic reprogramming using aerobic glycolysis (Warburg effect), is correlated with increased aggressiveness of cancer cells and poor outcome in patients. Therefore, genes involved in this pathway are promising targets for developing cancer therapeutics. Method: MIMs has developed a unique platform of augmented intelligence that combines bioinformatics, systems biology and artificial intelligence. It integrates multi-layered omics data with a knowledge-base that aggregates structured data from more than 140 databases as well as unstructured data from the scientific literature. Using this approach a genetic interaction graph (GI-Graph) is inferred per patient, capturing functional relationships between genes in the specific context of the tumor. The GI-Graphs are subsequently used to train supervised machine learning algorithms for predicting gene functionality and potential as a target. Preliminary analysis was performed on transcriptomic data from 321 LumA and 162 TNBC samples, from the TCGA Data Portal and a predictive model was developed using two GI-Graphs from the two subgroups. Briefly, subgraphs, containing genes with functional interactions with the known genes in OXPHOS and glycolysis pathways, were used to extract gene attributes, and to build an algorithm that predicts involvement of a gene in the Warburg effect. Using a testing gene set extracted from the literature the performance of the model was assessed, which showed a true positive rate of 18% and a false positive rate of 0.36%, and outperformed 5-times the classical bioinformatics tools. Results: This model predicted 108 genes as the top 1% genes being involved in the metabolic reprogramming of TNBC. Additional information from MIMs’ platform, including differential gene expression between LumA and TNBC, gene pleiotropy and essentiality and the topological metrics, enabled the life scientists to further refine the gene lists, based on the expected characteristics of a good target in oncology. Following this process, 30 genes were selected as potential targets controlling the metabolic reprogramming of TNBC, among which 4 genes were already evaluated in TNBC clinical trials. Conclusion: Our preliminary data strongly supports that the predictive model based on the GI-Graphs has the potential to identify promising therapeutic targets for TNBC. Citation Format: Sarah Jenna, Benjamin Boucher, Liebaut Dudragne, Abdoulaye Baniré Diallo. Augmented intelligence to define drug targets associated with triple negative breast cancer (TNBC) metabolic reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6375.
Abstract 5465: Discovery of LXRβ selective agonists promote immune cell activation and induce tumor growth inhibition in syngeneic tumor model
Authors: Brahmam Pujala, Balaji Dashrath Sathe, Ashu Gupta, Abhinandan Danodia, Sanjeev Soni, Vivek Kumar, Uzma Saeed, Sarvajit Chakravarty
Journal: Cancer Research (2022)

Abstract Nuclear receptors, liver X receptor-α (LXRα) and liver X receptor-β (LXRβ), are considered master regulators of lipid homeostasis and play pivotal roles in several physiological and pathological processes ranging from energy supply, cardiovascular, immunity, neurodegenerative disorders and cancer. Therapeutic agonism of the LXR/ApoE axis has proven to promote anti-tumor immunity by targeting immunosuppressive innate immune cells.1 LXR-ApoE pathway regulate the innate immune system in cancer, via modulation of the activity and abundance of myeloid derived suppressor cells (MDSC) and DCs. ApoE binds to Lipoprotein receptor-related protein (LRP) on MDSC induces apoptosis, thus resulting in immune-mediated anti-tumor activity of LXR agonists. Development of LXR agonists as therapeutics has proven quite challenging due to their precipitation of hepatic steatosis and hypertriglyceridemia. Most of the lipogenic effects of LXR agonists are mediated through LXRα.2 LXR subtype-specific agonists (LXRβ specific), may overcome hepatic triglyceride accumulation and (transient) hypertriglyceridemia. Here we report the discovery of IBS624 which is the most selective LXR agonist till date, &amp;gt;185X selective for LXRβ over LXRα. IBS-624 has reasonable exposure in mouse with 40% oral bioavailability. IBS-624 was well tolerated at 100mg/kg, BID for 14 days with no increase in triglycerides and neutropenia. IBS-624 has shown efficacy in MC38 colon cancer model as single agent as well as in combination with Checkpoint inhibitor. 1. Cell. 2018, 172(4): 825-840. 2. Biochemical pharmacology 2006, 71, 453-463 Citation Format: Brahmam Pujala, Balaji Dashrath Sathe, Ashu Gupta, Abhinandan Danodia, Sanjeev Soni, Vivek Kumar, Uzma Saeed, Sarvajit Chakravarty. Discovery of LXRβ selective agonists promote immune cell activation and induce tumor growth inhibition in syngeneic tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5465.
Abstract 3155: "Super NK cells" - natural killer cells derived from engineered hiPSC with enhanced NK receptor expression demonstrate better anti-tumor effects for solid tumors
Authors: Yiyun Wang, Xiangjun He, Linqin Wang, Mi Shao, Yanan Yue, Yangbin Gao, George Church, He Huang, Luhan Yang
Journal: Cancer Research (2022)

Abstract CAR-T cells expressing chimeric antigen receptors (CAR) have shown clinical success for treating hematologic malignancies, but their efficacy in solid tumors has been limited, largely due to tumor heterogeneity and immunosuppressive tumor microenvironment (TME). Natural Killer (NK) cells derived from human induced pluripotent stem cells (hiPSC) hold great potential to become the next-generation cell therapy products because of their established safety profile and their unique biological activities, especially their potential effectiveness for targeting solid tumor. In contrast to T cells, NK cells exert anti-tumor activity without requiring antigen recognition through MHC complex; they are instead activated by calculated signaling through ligation of multiple activating and inhibitory receptors. As various solid tumors highly express activation ligands for NK cells, we reason that enhanced expression of activation receptors on NK cells could improve their killing activity towards solid tumors. Here, we report that “super NK cells” with more than 10 folds higher expression of NK cell receptors such as NKG2D and NCRs derived from engineered hiPSC show improved cytotoxicity against solid tumors compared with non-engineered ones. The “super NK cells” can achieve more than ten rounds of serial killing against both K562 and THP-1 cell lines in vitro. More importantly, the “super NK cells” show improved cytotoxicity to multiple solid tumors in both in vitro system and in vivo xenograft mouse models. In summary, we have engineered hiPSCs which can be differentiated into "super NK cells" as a potential cell therapy product for improved efficacy against solid tumors. Citation Format: Yiyun Wang, Xiangjun He, Linqin Wang, Mi Shao, Yanan Yue, Yangbin Gao, George Church, He Huang, Luhan Yang. "Super NK cells" - natural killer cells derived from engineered hiPSC with enhanced NK receptor expression demonstrate better anti-tumor effects for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3155.
Abstract 1343: CD8+ resident memory T (TRM) cells in tumors
Authors: Fathia Mami-Chouaib
Journal: Cancer Research (2022)

Abstract Tumor-resident memory T (TRM) cells play an important role in cancer diseases. Accumulating evidence indicates that subpopulations of CD3+CD8+ tumor-infiltrating lymphocytes (TIL) are TRM cells, and are emerging as activated tumor-specific T cells. These TRM cells are characterized by expression of CD103 integrin and identify tumor-reactive cytotoxic T lymphocytes (CTL). Human lung tumor CD103+CD8+ TRM cells co-express CD49a and CD69, and are associated with a favorable prognosis. They also express a panel of T-cell inhibitory receptors, including PD-1, and are able to kill autologous tumor cells upon blockade of PD-1 with neutralizing antibodies. This CD103+CD8+ TRM subset also emerges as a predictive biomarker of response to PD-1 blockade and expands during anti-PD-1 treatment in responder, but not in non-responder lung cancer patients. It is now widely admitted that expression of CD103 on activated CD8+ T lymphocytes and persistence of TRM cells in epithelial tissues requires transforming growth factor (TGF)-β. This cytokine is secreted in the tumor microenvironment in its inactive form bound to latency-associated protein (LAP), and is activated by αV integrins on tumor cells and immune cells. Using multiplex immunofluorescence staining on cohorts of anti-PD-(L)1-treated lung cancer patients, we recently showed that decreased expression of tumor αV is associated with improved immunotherapy-related-progression-free survival (PFS) and correlates with an increased density of CD8+CD103+ TIL. Cancer cell αV activates autocrine TGF-β and participates in inducing CD103 on activated CD8+ T cells. Our more recent studies in mouse tumor models and human cancers demonstrate that different CD8+ TRM subsets participate to response different immune checkpoint inhibitors and therapeutic cancer vaccines. Citation Format: Fathia Mami-Chouaib. CD8+ resident memory T (TRM) cells in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1343.
Screening for Glaucoma in Adults
Authors: Roger Chou, Shelley Selph, Ian Blazina, Christina Bougatsos, Rebecca Jungbauer, Rongwei Fu, Sara Grusing, Daniel E. Jonas, Shandiz Tehrani
Journal: JAMA (2022)

<h3>Importance</h3> Two 2013 systematic reviews to inform the US Preventive Services Task Force (USPSTF) found insufficient evidence to assess benefits and harms of screening for primary open-angle glaucoma (OAG) in adults. <h3>Objective</h3> To update the 2013 reviews on screening for glaucoma, to inform the USPSTF. <h3>Data Sources</h3> Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews (to February 2021); surveillance through January 21, 2022. <h3>Study Selection</h3> Randomized clinical trials (RCTs) of screening, referral, and treatment; and studies of screening test diagnostic accuracy. <h3>Data Extraction and Synthesis</h3> One investigator abstracted data and a second checked accuracy. Two investigators independently assessed study quality. <h3>Results</h3> Eighty-three studies (N = 75 887) were included (30 trials and 53 diagnostic accuracy studies). One RCT (n = 616) found screening of frail elderly persons associated with no difference in vision outcomes vs no screening but with significantly greater falls risk (relative risk [RR], 1.31 [95% CI, 1.13-1.50]). No study evaluated referral to an eye health professional. For glaucoma diagnosis, spectral domain optical coherence tomography (providing high-resolution cross-sectional imaging; 15 studies, n = 4242) was associated with sensitivity of 0.79 (95% CI, 0.75-0.83) and specificity of 0.92 (95% CI, 0.87-0.96) and the Humphrey Visual Field Analyzer (for perimetry, or measurement of visual fields; 6 studies, n = 11 244) with sensitivity of 0.87 (95% CI, 0.69-0.95) and specificity 0.82 (95% CI, 0.66-0.92); tonometry (for measurement of intraocular pressure; 13 studies, n = 32 892) had low sensitivity (0.48 [95% CI, 0.31-0.66]). Medical therapy for ocular hypertension and untreated glaucoma was significantly associated with decreased intraocular pressure and decreased likelihood of glaucoma progression (7 trials, n = 3771; RR, 0.68 [95% CI, 0.49-0.96]; absolute risk difference −4.2%) vs placebo, but 1 trial (n = 461) found no differences in visual acuity, quality of life, or function. Selective laser trabeculoplasty and medical therapy had similar outcomes (4 trials, n = 957). <h3>Conclusions and Relevance</h3> This review found limited direct evidence on glaucoma screening, showing no association with benefits. Screening tests can identify persons with glaucoma and treatment was associated with a lower risk of glaucoma progression, but evidence of improvement in visual outcomes, quality of life, and function remains lacking.
Abstract 2921: Probing PRMT5 inhibitors with distinct binding modes using surface plasmon resonance
Authors: Rebecca Eells, Lynn K. Baker, Christopher Bray, Haiching Ma
Journal: Cancer Research (2022)

Abstract Epigenetic modifications are dynamic and reversible processes that regulate gene expression without altering the underlying sequence of the DNA. Gene expression is instead controlled by modification to the chromatin including DNA methylation, histone modifications, and chromatin remodeling. The proteins that perform these epigenetic modifications can be divided into three classes: writers, which perform the modifications; readers, which recognize the modifications; and erasers, which remove the modifications. While essential for normal cellular function, abnormal expression or alteration of the proteins involved in epigenetic regulation can lead to disease, such as cancer. As a result, epigenetic modifiers present attractive targets for the discovery and development of novel therapeutics. At Reaction Biology we offer a suite of services to enable epigenetic drug including the largest panel for epigenetic screening and profiling in the industry and biochemical and biophysical technologies to evaluate inhibition, potency, target occupancy, and even binding modes. Here we highlight our biophysical platform surface plasmon resonance (SPR) using the epigenetic target PRMT5 as an example. SPR was used to measure the binding kinetics of several small molecule inhibitors of PRMT5 and explore their distinct binding modes. Citation Format: Rebecca Eells, Lynn K. Baker, Christopher Bray, Haiching Ma. Probing PRMT5 inhibitors with distinct binding modes using surface plasmon resonance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2921.
Manjula Arora case: the GMC stumbles again?
Authors: Partha Kar
Journal: BMJ (2022)

Disposition and metabolism of the new anticonvulsant 2,6-dimethylbenzamide <i>N</i>-(5-methyl-3-isoxazolyl) (D2916) was studied in male and female rats after oral administration of<sup>14</sup>C-labeled material. D2916 was well absorbed in both sexes and distributed to all tissues, with maximal drug concentrations found in elimination and metabolization organs, as well as in fatty tissues. Striking differences in pharmacokinetic parameters of total radioactivity were observed between males and females: females had higher brain concentrations and longer blood and tissue half-lives. The study of blood, bile, urine, and brain metabolites showed that D2916 follows two degradation pathways related to hydroxylation of methyl groups. Males prefer to hydroxylate one of the methyl groups of the phenyl ring, and females prefer to hydroxylate the methyl of the isoxazolyl ring forming the active metabolite D3187. These findings suggest a sex difference in the location of the hydroxylation of the D2916 molecule and can explain the longer anticonvulsant effect observed in the female rat that is related both to an orientation of the metabolism toward the formation of the active metabolite and to a better ability to this metabolite to cross the blood-brain barrier, compared with the unchanged drug.
Endovascular Treatment Versus Best Medical Management in Acute Basilar Artery Occlusion Strokes: Results From the ATTENTION Multicenter Registry
Authors: Chunrong Tao, Adnan I. Qureshi, Yamei Yin, Jie Li, Rui Li, Pengfei Xu, Jun Sun, Geng Liao, Xincan Yue, Hongchao Shi, Yongchang Liu, Zhengfei Ma, Jinhua Zhang, Guodong Xiao, Bo Xu, Chenghua Xu, Junfeng Su, Wensheng Zhou, Shuchun Huang, Weimin Yang, Hongbing Chen, Wei Li, Yongkun Li, Dezhi Liu, Chuanqing Yu, Guangxiong Yuan, Chaobin Wang, Wenbao Liang, Chun Chen, Xueying Shi, Junjun Wang, Yingchun Wu, Xueli Cai, Chunyun Shen, Kai Li, Pu Fang, Ming Wang, Zhongjun Chen, Tong Li, Guangsen Cheng, Yaxuan Sun, Yan Wang, Hui Zhang, Jie Chen, Xiaohui Xu, Youmeng Wang, Wanjie Geng, Chuyuan Ni, Changchun Chen, Yan Liu, Jie Min, Yongcheng Zhang, Yong Liang, Chao Wen, Blaise W. Baxter, Raul G. Nogueira, Wei Hu
Journal: Circulation (2022)

Background: The authors compare the effectiveness and safety of endovascular treatment (EVT) versus best medical management (BMM) in strokes attributable to acute basilar artery occlusion (BAO). Methods: The present analysis was based on the ongoing, prospective, multicenter ATTENTION (Endovascular Treatment for Acute Basilar Artery Occlusion) trial registry in China. Our analytic sample comprised 2134 patients recruited at 48 sites between 2017 and 2021 and included 462 patients who received BMM and 1672 patients who received EVT. We performed an inversed probability of treatment weighting analysis. Qualifying patients had to present within 24 hours of estimated BAO. The primary clinical outcome was favorable functional outcome (modified Rankin Scale score, 0–3) at 90 days. We also performed a sensitivity analysis with the propensity score matching–based and the instrumental variable–based analysis. Results: In our primary analysis using the inversed probability of treatment weighting–based analysis, there was a significantly higher rate of favorable outcome at 90 days among EVT patients compared with BMM-treated patients (adjusted relative risk, 1.42 [95% CI, 1.19–1.65]; absolute risk difference, 11.8% [95% CI, 6.9–16.7]). The mortality was significantly lower (adjusted relative risk, 0.78 [95% CI, 0.69–0.88]; absolute risk difference, −10.3% [95% CI, −15.8 to −4.9]) in patients undergoing EVT. Results were generally consistent across the secondary end points. Similar associations were seen in the propensity score matching–based and instrumental variable–based analysis. Conclusions: In this real-world study, EVT was associated with significantly better functional outcomes and survival at 90 days. Well-designed randomized studies comparing EVT with BMM in the acute BAO are needed. Registration: URL: www.chictr.org.cn ; Unique identifier: ChiCTR2000041117.
Abstract 2098: Practical cell counting method selection to increase the quality of cell counting results
Authors: Leo Chan, Jordan Bell, Bo Lin
Journal: Cancer Research (2022)

Abstract The importance of cell counting has increased significantly in the last decade due to the major advances in the fields of cell and gene therapy, biologics production, and regenerative medicine. This has necessitated the development of a standardized approach to cell counting assays. In recent years, the U.S. Food and Drug Administration (FDA), in collaboration with the National Institute of Standards and Technology (NIST) and the International Organization for Standardization (ISO), has launched an effort to standardize cell counting methods to improve the confidence in cell counting measurements. There is a wide range of biological sample types, various formulations, and bioprocessing steps for cell and gene therapy products. Furthermore, there are no ground truth reference materials for live cells, making the determination of accuracy of cell counting difficult defined in the ICH Q2 (R1). Therefore, in order to increase the confidence of cell counting results, it is critical to follow the two recently published ISO cell counting standards to ensure cell counting methods are tailored to the specific sample and purpose.In this work, we will provide insights and guidance for the ISO standards for method selection. The important aspects of the ISO cell counting standards have been distilled to six key factors for selecting the cell counting methods. Attention to these details will allow researchers to more easily adhere to the ISO recommendations to ensure high quality cell counting measurements, and in doing so, sites can meticulously document their rationale, process, and data results. Citation Format: Leo Chan, Jordan Bell, Bo Lin. Practical cell counting method selection to increase the quality of cell counting results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2098.
Abstract LB545: Structure, dynamics and consequences of replication stress-induced structural variants in hepatocellular carcinoma
Authors: Quentin Bayard, Pierre Cordier, Camille Péneau, Sandrine Imbeaud, Theo Z. Hirsch, Victor Renault, Jean-Charles Nault, Jean-Frédéric Blanc, Julien Calderaro, Chantal Desdouets, Jessica Zucman-Rossi, Eric Letouzé
Journal: Cancer Research (2022)

Abstract Oncogene activation leads to replication stress and promotes genomic instability. Here we combine optical mapping and whole genome sequencing to explore in-depth the nature of structural variants (SVs) induced by replication stress in cyclin-activated hepatocellular carcinomas (CCN-HCC). In addition to classical tandem duplications, CCN-HCC display frequent intra- and inter-chromosomal templated insertion cycles (TIC) likely resulting from template switching events. Template switching preferentially involves active topologically associated domains that are close in the 3D genome organization. Template sizes depend on the type of cyclin activation and are coordinated within each TIC. Replication stress induces continuous accumulation of SVs during CCN-HCC progression, fostering the acquisition of new driver alterations and large-scale copy-number changes at TIC borders. Together, this analysis sheds light on the mechanisms, dynamics and consequences of SV accumulation in tumors with oncogene-induced replication stress. Citation Format: Quentin Bayard, Pierre Cordier, Camille Péneau, Sandrine Imbeaud, Theo Z. Hirsch, Victor Renault, Jean-Charles Nault, Jean-Frédéric Blanc, Julien Calderaro, Chantal Desdouets, Jessica Zucman-Rossi, Eric Letouzé. Structure, dynamics and consequences of replication stress-induced structural variants in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB545.